There is a high failure rate of PhIII Cancer trials. One of the main reasons is inadequate or irrelevant information from PhII studies.

1. CHALLENGES IN PHASE
III CANCER CLINICAL
TRIALS
NOT ADEQUATE INFORMATION
FROM PHASE II
Dr. Bhaswat S. Chakraborty
Senior Vice President, R&D
Cadila Pharmaceuticals Ltd.
1
Presented at the 2nd National Conference (NCIP) on
“Emerging Trends in Drug Discovery, Development
and Molecular Targets for Cancer Research” at Nirma
Univ., Ahmedabad, India, 24-25 January, 2017

2. CONTENTS
 Clinical trial conduct & data
 Clinical Development Success & Consequences of Failure
 Why examine Failure Reasons
 Inadequate Ph II Information
 Sample size
 Single arm studies
 Historical control
 Problems with Historical Controls
 Patient heterogeity
 End point consideration
 Remedies
 Concluding remarks
2

3. Investigational
Sites
Product
Management
Project
Management
Drug & Clinical Trial Development
Extended Picture
IRB Regulatory
Documents
Relationship
Building
eMails
Partners &
Affiliates
Meetings
CROs
Contracts
Knowledge
Information
Safety
Communication
Resource
Management
Data Capture
Data Management
Multidirectional Flow of Activities, Data and Decisions
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4. CLINICAL DEVELOPMENT
SUCCESS RATE
Of the 14 major disease areas,
Likelihood of Approval (LOA):
Oncology had the lowest (5.1%)
Hematology had the highest (26.1%)
Sub-indication analysis within Oncology
revealed hematological cancers had 2x
higher LOA
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Bio-Industry Analysis June 2017

5. 5
Consequences of failure can be very dramatic

6. MOST COMMON REASONS OF
PHASE III ONCO TRIAL
FAILURE
 Lack of efficacy
 Lack of Safety
 Very rarely Quality
 Commercial/Financial/Administrative
6

7. WHY EXAMINE THE CAUSES OF
FAILURE?
 Discoverer or Investigator: difficult personal experience
given non-clinical data promising
 Ethical: Why thousands of patients were exposed to a
compound that did not provide a possibility for clinical
improvement
 Cancer is the 2nd leading cause of mortality in the US
 Successful development is relevant not only to
professionals but to the general public as well
 Potentially huge savings in resources
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8. WHAT DOES THE LITERATURE
SAY (RE CAUSES OF FAILURE?)
 “Negative” findings are typically not published or are
published after a substantial delay
 Even when published, crucial elements of the study
e.g., statistical design are often missing
 Original analysis missing, only a retrospectively-
defined analysis provided
 to have clues or new direction for future research
 Gap between +ve & -ve study publications:,
 a survey of reported breast cancer Phase 2 studies found
that 80% had positive outcome [Perone F et al. (2003). Lancet 4:305-311]
 However, ClinicalTrials.gov can give you some
insight
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9. BASICS OF PHASE III FAILURE
9
False positive from Ph
II: Phase 2,Test is safe
& efficacious in targeted
population,
while the reverse is
true
Wrong design and
implementation of the
Ph III,
Sample size, patient
heterogeneity, wrong
end-point etc. …
Retzios AD (2009) Bay Clin R&D Services

10. WRONG INFORMATION FROM
PH II
 In all areas – Efficacy, Safety, Patient population &
sample size, Randomization, Hypotheses, Outcome
variables, Levels of α or β, Dose..
 Many reasons for inaccuracies all the above areas
 Of all phases of CTs, Ph II trials are more likely to
give false positives
 Any inaccurate information from this phase enhances
the possibility of failure in Ph III
 Efficacy based Ph II dose ranging study may be
required
 Toxicity-wise dose ranging study may not make sense
10
Retzios AD (2009) Bay Clin R&D Services

11. SAMPLE SIZES
 Sample sizes are usually smaller (N<300) in Ph II
programs
11
 d is the tolerance interval of difference between the
outcome variable of test and control arms; usually
kept large e.g., 20-40%
 In actual Ph III studies the “clinical-benefit”
oriented endpoits e.g., OS show much smaller
margins
 Often re-examination and underpowered Ph II
studies false +ve

12. “Investigators consistently make
overly-optimistic assumptions
regarding treatment benefits when
designing RCTs.”
Gan HK et al (2012). J Natl Cancer Inst.,
104: 590-598
12

13. SINGLE ARM PH II STUDIES
 SA, Two-stage Ph II studies have been very common in
Onco
 Such oversimple design is based on assumptions:
 tumors are unlikely to regress without pharmacological
intervention
 although certain tumor types show high spontaneous regression rates
 % response for the standard treatment (which constitutes a
historical control) can be adequately defined
 Ph III success depend heavily of how well the
historical controls have been defined and
 Ph II conclusions in both stages therein are
overoptimistic & underpowered
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Retzios AD (2009) Bay Clin R&D Services

14. PROBLEMS WITH HISTORICAL
CONTROLS
 Historical controls are frowned upon and usually
discouraged by regulatory guidance outside Oncology
 Historical controls are not appropriate comparator for
data collected prospectively because of
 differences in concomitant treatment
 demographics
 study entry criteria
 time and type of assessments
 methodology of measurement
 number of other study provisions …
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Retzios AD (2009) Bay Clin R&D Services

15. WHY MULTI-ARM, RANDOMIZED
DESIGNS WITH ACTIVE OR PLACEBO
CONTROL ARE BETTER?
 Historical controls are inadequate or non-existent for
the newer cytostatic agents
 These agents do not result in tumor shrinkage but
may have a substantial impact on OS
 prohibit tumor growth and metastases
 but do not result in substantial tumor size reduction during
Ph II studies’ short observation period
 Since OS takes a number of years of observation, Ph
II RCTs of cytostatic agents normally utilize disease
progression endpoints
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16. PATIENT HETEROGENEITY
 Patient heterogeneity in small sized Ph II trials remains
a major challenge
 If relevant covariates (e.g., patient molecular
phenotype) are not balanced, a +ve or -ve difference
from control may reflect imbalance in these
covariates
 study: weekly docetaxel + trastuzumab vs weekly paclitaxel
plus trastuzumab in NSCLC
 randomized patients also stratified on HER-2 protein
expression (trastuzumab targets the HER-2/neu receptor)
 The study did not reveal any advantages for these
treatments, but the approach was valid
16

17. RANDOMIZED DISCONTINUATION
DESIGNS
 Two stage trial
 all patients are treated with the test
 patients with stable disease are then randomized to either
the test or control (placebo or current treatment)
 disease progression is assessed
 stage 1 ceases when calculated stage 2 randomized sample
size is achieved
 Essentially, these are enriched designs
 The resulting sample is more homogeneous
 reduces variance and increases power of thestudy
 Problems: the drug effect has been amplified &
blinding in stage 2 may be difficult if the active
treatment has a certain toxic profile
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18. END-POINT CONSIDERATIONS
 In Ph III, the primary endpoint must be well-defined and
show accepted clinical benefit (often OS)
 In Ph II, surrogate endpoints (usually pharmacodynamic or
disease progression) may be OK
 but not correspond directly to measurable clinical benefit
 Whereas provides strong evidence of pharmacological activity
 Ph II endpoints are usually speedier and less costly
 usually PFS, objective tumor response, TTP
 RECIST or WHO criteria tumor response correlates well with OS
for solid tumors &cytotoxic compounds
tumor response does not work for melanoma and
renal cell cancer and for cytostatic agents 18

19. PROBLEMS (& MERITS) OF TTP &
PFS
 In many cases Ph II PFS and TTP correlate with Ph III OS
outcome
 Works well for cytostatic anti-cancers
 Problems with PFS and TTP
 highly influenced by frequency of assessments
 Disease progression in period of observation (few mo to a yr)
is highly variable among patients
 Sometimes it is difficult to assign lack of progression to
drug’s pharmacological action
 both PFS and TTP are very susceptible to investigator bias
 cannot be used in non-randomized, multi-stage trials
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20. FAULTY CONDUCT OF PH II
STUDIES
 Many Ph II studies are inadequately conducted
 Numerous protocol violations and deviations
 protocol violations noted in ≥ 20% of enrolled subjects make the study
unreliable
 GCP violations are rampant across the globe
 Data integrity issues
 Sites and investigators are not appropriately trained
 Go/no go decisions are often strongly affected by the desire
to succeed at any cost
 PoCs are often Proof of Cleverness
 the therapeutic effect is overestimated & consequently, the pivotal
studies fail to achieve the desired endpoint
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21. COMPREHENSIVE FAILURE
TRIGGERS
Drivers of
Failure
Examples
Inadequate Basic
Science
•Beneficial effects in animal models
not reproduced in humans
•Poor understanding of target disease
biology
Flawed Study
Design
•Patient population definition changed
from phase –II to phase –III
•Phase –II surrogate endpoint not
confirmed by Phase-III clinical
outcomes
Suboptimal dose
selection
•Inadequate dose finding in Phase-II
•Poor therapeutic indices 21
Parexel

22. COMPREHENSIVE FAILURE
TRIGGERS..
Drivers of
Failure
Examples
Flawed data
collection and
analysis
• Phase-II false positive effects were not
replicated in Phase-III
•Overoptimistic assumptions on
variability and treatment difference
•Missing data; attrition bias; rater bias
•Wrong statistical tests; other statistical
issues
Problems with
study operations
•Data integrity issues; GCP violations
•Recruitment, dropouts, noncompliance
and protocol
•Missing data; unintentional unblinding
Other •Insufficient landscape assessment of
current standard of care and precedents.
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23. WELL DESIGNED PH II RCT
23
Belani, Chakraborty, Modi & Khamar (2016) Annals of Oncology

24. FRAMEWORK
Right Target
•Strong link between target and disease
•Differentiated efficacy
•Available and predictive biomarkers
Right Tissue
•Adequate bioavailability and tissue exposure
•Definition of PD biomarkers
•Clear understanding of pre-clinical and clinical PK/PD
•Understanding of drug-drug interactions
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Optimize a rational and effective the
entire Clinical Development process

25. ASTRAZENECA’S THE 5R
FRAMEWORK..
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•Differentiated and clear safety margins
•Understanding of secondary pharmacology risks
•Understanding of reactive metabolites, Genotoxicity, dr-dr interactions
•Understanding of target liability
Right Patients
•Identification of the most responsive patient population
•Definition of risk-benefit for given population
Right Commercial Potential
•Differentiated value proposition versus standard of care
•Focus on market access, payer and provider
•Personalized healthcare strategy, including diagnostic
and biomarkers
Right Safety

26. OTHER AREAS OF REDUCING
PHASE III FAILURE RISKS
 Replacement of the current gold standard, the
randomized controlled trial, with real-world evidence
 Wearable devices that collect real-time data
 Adaptive licensing
 Next-generation sequencing and improved
understanding of the genetic basis of disease
 Basket/master protocols
 Phase III failures cannot be eliminated, can only be
reduced 26

27. CONCLUDING REMARKS
 Well designed, properly conducted Ph II cancer RCTs can
provide a sound basis of go/no go for Ph III
 Careful evaluation of historical data, correct design and
sample size, appropriate end-point are some of the keys
 A good trade-off between completing Ph II in time and
obtaining accurate information is required
 Planning at Ph II level should include a clear idea as to
what needs to be achieved in the pivotal Ph III
 both in terms of the population to be treated & therapeutic advantage
to be sought
 A comprehensive clinical development & data integrity plan
helps
 Also awareness of the competitive environment and the
construction of a target label ae required
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28. THANK YOU VERY
MUCH
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